Regulation of receptor protein-tyrosine phosphatase α by oxidative stress

The presence of two protein-tyrosine phosphatase (PTP) domains is a striking feature in most transmembrane receptor PTPs (RPTPs). The function of the generally inactive membrane-distal PTP domain (RPTP-D2) is unknown. Here we report that an intramolecular interaction between the spacer region (Sp) and the C-terminus in RPTPα prohibited intermolecular interactions. Interestingly, stress factors such as H(2)O(2), UV and heat shock induced reversible, free radical-dependent, intermolecular interactions between RPTPα and RPTPα-SpD2, suggesting an inducible switch in conformation and binding. The catalytic site cysteine of RPTPα-SpD2, Cys723, was required for the H(2)O(2) effect on RPTPα. H(2)O(2) induced a rapid, reversible, Cys723-dependent conformational change in vivo, as detected by fluorescence resonance energy transfer, with cyan fluorescent protein (CFP) and yellow fluorescent protein (YFP) flanking RPTPα-SpD2 in a single chimeric protein. Importantly, H(2)O(2) treatment stabilized RPTPα dimers, resulting in inactivation. We propose a model in which oxidative stress induces a conformational change in RPTPα-D2, leading to stabilization of RPTPα dimers, and thus to inhibition of RPTPα activity.